Another Casualty in Antidepressant Development

Implications: The development of a new generation of serortinin 5HT1a agonists for major depression and anxiety disorders has met yet another failure, now from EPIX Pharmaceuticals’  PRX-00023.  Gepirone ER (GlaxoSmithKline), another 5HT1a partial agonist, suffered the same fate last November when the FDA rejected it as a treatment for depression.  The article cites poor efficacy in depression as the reason for dropping development of PRX-00023 though lack of efficacy for generalized anxiety disorder has been reported in the past with published results this month failing to show benefit over placebo on primary endpoints.  Does this failure offer any insights for what’s in the antidepressant pipeline or for other, similarly acting drugs?    

Analysis: Drugs acting primarily by way of this mechanism of action historically have a rather poor track record.  Buspirone, available for treatment of generalized anxiety disorder, is sparsely used nowadays despite some new data shedding light on its potential value to augment antidepressants.  Pindolol, an antihypertensive with 5-HT1a properties, has had mixed results in mood and anxiety studies.  As far as I can  tell,  PRX-00023 may have been the last 5HT1a partial agonist in development for depression or anxiety and perhaps deservedly so, though a number of companies (ie, Lundbeck, Fabre-Kramer, Clinical Data, among them) are betting that this receptor profile in combination with other serotonin receptor actions will add efficacy, improve side effect profile, or speed up response over the commonly prescribed class of SSRI’s.  GlaxoSmithKline has an early stage 5HT1a antagonist for mood and anxiety disorders; Vilazodone, in Phase III trials, could be the first-in-class mixed SRI/5HT1a  partial agonist and carries some favorable data.   While a bad blow for EPIX – having lost 50% of its valuation since the bad news a few weeks ago – one of their novel early stage CNS products, a 5HT6 antagonist, looks quite interesting for memory and weight problems.